This invention was funded at least in part by a grant and other support from The Department of Health and Human Services, and the Government has certain rights in this invention.
This invention relates to treating humans and animals to control serum transport of lipid-soluble compounds (particularly cholesterol, vitamin A and triglycerides) for example to treat deficiencies in transport, excretion and metabolism of lipid-soluble compounds or to redistribute lipid-soluble compounds among various tissues.
Lipophiles (i.e., compounds soluble in lipids, but not in water), including those which are normal constituents of the human body, become pathogenic agents when the organism lacks the ability to transport, excrete, metabolize, or redistribute them properly. Such functions, particularly those related to transport phenomena, may involve carrier proteins and cellular receptors.
In the case of cholesterol, naturally produced carrier proteins carry the lipophile and circulate in vascular and lymphatic systems until the lipophile is absorbed by cells. The carried lipophile is then used in cell metabolism. Absorption of carrier proteins by a cell is a regulated and specific process mediated by receptors which are located on the surface of cells which tightly bind the protein and serve in its internalization.
In the absence of appropriate carrier proteins or their receptors a disease state is established. Cholesterol, a vital substance, when deposited into an arteriosclerotic plaque is converted into a causative agent of a family of often fatal vascular diseases. While cholesterol deposits in the vascular system are being formed, other tissues maintain continued cholesterol synthesis and thus further aggrevate the disease.
Other examples of human disease (including the toxicity of fat-soluble vitamins) relate to excess circulating levels or excess tissue loading of lipophiles. Vitamin D has been used in large dosages to treat various forms of metabolic disorders, including hypoparathyroidism and vitamin D resistance syndromes. As there is a narrow margin between the therapeutic and toxic dosages of vitamin D in many of these disorders, toxicity from vitamin D has frequently occurred. Another condition which may be related to an increased sensitivity to vitamin D or abnormal accumulation of its metabolites is the Williams syndrome, or idiopathic hypercalcemia of infancy.
Another serious disorder is hypervitaminosis A. Several serious problems are involved in the use of a synthetic carriers to control lipophile transport in serum. To be useful as a therapeutic, a transfer agent must have a demonstratable, quantitative effect at relatively low concentration levels. Specifically, the carrier must be able to transport the lipophile, when present in regulated, adaptable concentrations, far below the concentrations suggested by stoichiometric matching with normal serum lipophile levels. For example, serum concentrations of cholesterol in humans may vary from about 100-400 mg/dl, whereas triacylglycerol concentrations may vary from 60-1200 mg/dl. Thus, the range of variation for these two lipophiles alone is about 1400 mg/dl. In vitro solubilization of cholesterol using a carrier such as a cyclodextrin requires about ten times their excess weight of cyclodextrins. If that ratio were to apply in vivo, about one pound of solubilizer would have to be infused into a man just to make up for the normal range variation; a situation clearly impossible. Moreover, the situation is further complicated by the presence of lipophiles in various tissues at concentrations well in excess of the serum levels. This tissue could act as a reservoir, supplying lipophile to the blood stream and thus overwhelming any synthetic carrier.